description): The proposed research will address the regulation of myocardial oxidative phosphorylation at maximal energy expenditure rates (induced by inotropic stimulation) in hearts with severe post-infarction left ventricular remodeling (LVR). The primary focus is to study the role of oxygen and carbon substrate delivery by blood flow, along with creatine levels and activities of creatine kinase isoforms, in regulating oxidative phosphorylation and the energy charge of the myocyte. The applicant will perform experimental measurements of the progression of LVR with a unique combination of MRS and MRI in the closed chest pig model, with each study culminating in acute studies on the open chest pig to determine the bioenergetics and tissue oxygenation levels across the LV wall, along with more traditional measurements of regional blood flow with radiolabeled, tracer microspheres and metabolic parameters with biochemical an immunoassay methods. The applicant proposes this approach to test six hypotheses: The first is that oxygen delivery to mitochondria is not limiting oxygen consumption rate and, as such, does not limit ATP turnover at maximal workloads. The second is that at very high workstates, carbon substrate delivery by blood flow is limiting the rate of oxygen consumption, but that carbon substrate metabolism becomes a controlling factor in determining mitochondrial NADH production. Part of this hypothesis is also that hearts with LVR are more vulnerable to high workstate stress. The third hypothesis is that in the failing heart, inotropic response to elevated cAMP impairs energy reserve. The fourth is that mitochondrial uncoupling causes increased MVO2 in normal hearts, but fails to increase MVO2 in failing hearts, reflecting exhaustion of myocardial energy reserve. The fifth hypothesis is that reduced myocardial creatine levels may contribute to reduced PCr levels and creatine kinase flux in LVR, which contribute to bioenergetic and functional abnormalities. The applicant hypothesizes that chronic creatine supplementation will increase PCr levels and CK flux as a beneficial effect on the remodeling process. The final hypothesis is that late reopening of the infarct-related coronary artery has beneficial effects that are associated with amelioration of bioenergetic abnormalities that result from reduced LV wall stresses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050470-07
Application #
6389289
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Dunn, Rosalie
Project Start
1993-07-05
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
7
Fiscal Year
2001
Total Cost
$259,592
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Chen, Yong; Ye, Lei; Zhong, Jia et al. (2015) The Structural Basis of Functional Improvement in Response to Human Umbilical Cord Blood Stem Cell Transplantation in Hearts With Postinfarct LV Remodeling. Cell Transplant 24:971-83
Zhu, Xiao-Hong; Qiao, Hongyan; Du, Fei et al. (2012) Quantitative imaging of energy expenditure in human brain. Neuroimage 60:2107-17
Xiong, Qiang; Ye, Lei; Zhang, Pengyuan et al. (2012) Bioenergetic and functional consequences of cellular therapy: activation of endogenous cardiovascular progenitor cells. Circ Res 111:455-68
Wang, Xiaohong; From, Arthur H L; Zhang, Jianyi (2012) Myocardial regeneration: the role of progenitor cells derived from bone marrow and heart. Prog Mol Biol Transl Sci 111:195-215
Kamdar, Forum; Jameel, Mohammad Nurulqadr; Score, Paul et al. (2012) Cellular therapy promotes endogenous stem cell repair. Can J Physiol Pharmacol 90:1335-44
Xiong, Qiang; Hill, Katherine L; Li, Qinglu et al. (2011) A fibrin patch-based enhanced delivery of human embryonic stem cell-derived vascular cell transplantation in a porcine model of postinfarction left ventricular remodeling. Stem Cells 29:367-75
Xiong, Qiang; Du, Fei; Zhu, Xiaohong et al. (2011) ATP production rate via creatine kinase or ATP synthase in vivo: a novel superfast magnetization saturation transfer method. Circ Res 108:653-63
Jameel, Mohammad Nurulqadr; Li, Qinglu; Mansoor, Abdul et al. (2011) Long-term preservation of myocardial energetic in chronic hibernating myocardium. Am J Physiol Heart Circ Physiol 300:H836-44
Lee, Joseph; Hu, Qingsong; Mansoor, Abdul et al. (2011) Effect of acute xanthine oxidase inhibition on myocardial energetics during basal and very high cardiac workstates. J Cardiovasc Transl Res 4:504-13
Jameel, Mohammad Nurulqadr; Zhang, Jianyi (2010) Stem cell therapy for ischemic heart disease. Antioxid Redox Signal 13:1879-97

Showing the most recent 10 out of 16 publications